Document Detail

Expression of nonmuscle cofilin-1 and steroid responsiveness in severe asthma.
MedLine Citation:
PMID:  17088134     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Glucocorticoids are the mainstay of asthma therapy; however, a proportion of patients with asthma has a severe form of the disease that fails to respond to therapy. Understanding the molecular mechanisms behind glucocorticoid-insensitive asthma is therefore of clinical importance. Evidence in glucocorticoid-unresponsive Henrietta Lack (HeLa) cells indicated that cofilin-1 could act as an inhibitor of glucocorticoid function. OBJECTIVE: To determine whether cofilin-1 expression is abnormally expressed in cells from patients with severe glucocorticoid-insensitive asthma and examine the effect of cofilin-1 overexpression on glucocorticoid function. METHODS: Peripheral blood CD4(+) T cells were purified from 16 subjects with severe glucocorticoid-insensitive asthma and 16 subjects with mild glucocorticoid-sensitive asthma, and cofilin-1 expression was determined by quantitative real-time RT-PCR and Western blotting. The effect of dexamethasone on cofilin-1 expression was determined in Jurkat T cells, and the effect of cofilin-1 overexpression on anti-CD3/CD28-stimulated IL-2 release was measured. RESULTS: Peripheral blood CD4(+) T cells from subjects with severe glucocorticoid-insensitive asthma are less responsive to dexamethasone than cells from subjects with mild glucocorticoid-sensitive asthma. Cells from these patients express significantly (P < .05) higher levels of cofilin-1 than cells from subjects with mild asthma. Dexamethasone did not affect cofilin-1 expression in Jurkat T cells. Functionally, dexamethasone suppression of anti-CD3/CD28-stimulated IL-2 was attenuated in Jurkat cells overexpressing cofilin-1. CONCLUSION: These results suggest that increased cofilin-1 expression may be important in the regulation of glucocorticoid sensitivity in peripheral blood lymphocytes of patients with severe treatment-insensitive asthma. CLINICAL IMPLICATIONS: Understanding the mechanisms of enhanced cofilin-1 expression may lead to the development of new therapies for severe treatment-insensitive asthma.
Nisha Vasavda; Thomas Eichholtz; Atsushi Takahashi; Karen Affleck; John G Matthews; Peter J Barnes; Ian M Adcock
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-25
Journal Detail:
Title:  The Journal of allergy and clinical immunology     Volume:  118     ISSN:  0091-6749     ISO Abbreviation:  J. Allergy Clin. Immunol.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-07     Completed Date:  2006-12-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  1275002     Medline TA:  J Allergy Clin Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1090-6     Citation Subset:  AIM; IM    
Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK.
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MeSH Terms
Asthma / drug therapy*,  metabolism*,  physiopathology
CD4-Positive T-Lymphocytes / drug effects,  metabolism
Cells, Cultured
Cofilin 1 / biosynthesis*,  genetics*
Cytokines / antagonists & inhibitors,  metabolism,  secretion
Dexamethasone / antagonists & inhibitors,  pharmacology*
Forced Expiratory Volume / drug effects
Glucocorticoids / pharmacology*
Immunosuppressive Agents / antagonists & inhibitors,  pharmacology
Jurkat Cells
Middle Aged
Severity of Illness Index*
Reg. No./Substance:
0/Cofilin 1; 0/Cytokines; 0/Glucocorticoids; 0/Immunosuppressive Agents; 50-02-2/Dexamethasone

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